This invention relates to inhibition of psychostimulant-induced or nicotine-induced craving in humans.
The use of psychostimulants, such as cocaine, and of nicotine often leads to repeated use and a profound state of addiction in humans, which is characterized by compulsive drug use and an inability to control use despite significant adverse consequences. Cocaine, for example, is one of the most reinforcing drugs known (Johanson et al., 1989, Pharmacol. Rev. 41:3-52). Progress toward understanding the neural substrates of addiction to cocaine and other addictive drugs has mostly been limited to research with animal models. The use of such animal models, however, has been limited by the inability to correlate observed patterns of brain activation with subjective information about emotional and cognitive responses to drugs, such as euphoria or craving typically experienced after use of addictive drugs.
It has now been shown that a distinct pattern of brain activation is exhibited by humans during periods of craving induced by a psychostimulant. As determined by functional magnetic resonance imaging (fMRI), psychostimulant-induced craving (e.g., cocaine-induced craving) is strongly correlated with early, but sustained, signal changes (positive or negative) in the nucleus accumbens and in the amygdala. In contrast, as shown below, the cocaine-induced experience of rush is associated with a pattern of brain activation distinct from the pattern exhibited during cocaine-induced craving. As discussed in further detail below, the studies described herein demonstrate that (a) humans have the same extended neural network of reward circuitry as animals, and (b) this circuitry performs both reinforcement reward and incentive reward function (e.g., craving). These observations, along with (1) observations from animal studies, showing that drugs specific for D1 receptors alter reward processes in the brain and (2) observations regarding the distribution of dopamine receptor subtypes in the brain, indicate that agonists and antagonists of the D1-like receptors can be used to inhibit craving of psychostimulants in humans, with or without inhibition of euphoria. In addition, such agonists and antagonists can be used to inhibit craving of the stimulant nicotine, which is associated with intense craving and is predicted to induce patterns of brain activation that parallel those seen with psychostimulants such as cocaine.
Without being bound to any particular theory or mechanism, D1-like agonists (also referred to herein as xe2x80x9cD1-like receptor agonistsxe2x80x9d) are thought to provide some or all of the sensations of rush and high associated with the use of a psychostimulant or nicotine, without leading to significant levels of further drug craving. Although a patient treated with a D1-like agonist may consume an initial quantity of a psychostimulant or nicotine, further craving of the addictive drug will be inhibited, thereby inhibiting binge-like drug consumption. D1-like antagonists are thought to inhibit initial cravings for psychostimulants or nicotine or to reduce the euphoria felt from psychostimulants or nicotine, thereby inhibiting the initiation of binge-like behavior.
Accordingly, the invention features a method for inhibiting a psychostimulant-induced craving in a human, which method entails identifying the human as being psychostimulant-dependent, and administering to the human a D1-like antagonist or D1-like agonist in an amount effective to inhibit craving of the psychostimulant. In various embodiments, the psychostimulant may be cocaine (including crack cocaine) or amphetamine.
In a related method, the invention features a method for inhibiting a nicotine-induced craving in a human, which method entails identifying the human as being nicotine-dependent, and administering to the human a D1-like antagonist or D1-like agonist in an amount effective to inhibit craving of nicotine (e.g., craving of nicotine-containing cigarettes). Typically, in practicing the methods of the invention, the patient (i.e., human) is a compulsive user of the psychostimulant or nicotine. The methods of the invention are particularly useful in inhibiting drug-induced craving, which is the craving experienced after drug use (e.g., within 15 seconds to 120 minutes).
Now that, as shown by the experiments described below, the psychostimulant-induced patterns of brain activation in humans and rodents are known to overlap each other closely, rodents (e.g., rats and mice (including knockout mice, such as knockouts of the D1 receptor or DAT transporter)) can be used as animal model systems for measuring the ability of a test compound to inhibit psychostimulant-induced or nicotine-induced craving in a human. This method of the invention entails administering the test compound to a rodent; administering a psychostimulant or nicotine to the rodent; and measuring an attenuation in the level of brain activation in the rodent subsequent to administration of (a) the test compound and (b) the psychostimulant or nicotine, as compared with the level of brain activation obtained upon (a) administration of the psychostimulant or nicotine to the rodent without (b) administration of the test compound, as a measure of the ability of the test compound to inhibit psychostimulant-induced or nicotine-induced craving in a human. In various embodiments, the psychostimulant can be cocaine (including crack cocaine) or amphetamine. The animal may be drug-naive, or it may be chronically addicted to a psychostimulant or nicotine by virtue of its having been repeatedly treated with the drug previously. Useful animal models of chronic addiction include, without limitation, (a) animals taught to self-administer drugs and (b) condition-place preference paradigms (where the readiness of an animal to go to a place where the animal has previously had the drug is measured). The test compound can be a known D1-like agonist or D1-like antagonist (such as those described herein), or it may be any compound of interest, such as uncharacterized small organic molecules of interest. The test compound typically is administered at a dosage of 0.0001 to 100 mg/kg of the body weight of the rodent. Typically, the test compound is administered to the animal 0 minutes to 2 days (e.g., 15 minutes to 8 hours) prior to administration of the psychostimulant or nicotine to the animal. The test compound can be administered to the animal in a single dose or in repeated doses (e.g., 1, 2, or 5 or more times daily) prior to administration of the psychostimulant or nicotine. The decrease in the level of brain activation can be measured by any of the various methods for measuring brain activations, such as functional MRI (with or without contrast agents such as monocrystalline iron oxide nanocolloid (MION) particles or gadolinium) and laser Doppler-flowmetry, as described above for example.
Examples of suitable D1-like antagonists for use in the methods of the invention include SCH 39166; SCH 23390; A-69024; bulbocapnine; butaclamol HCl, (+)-; fluphenzanine HCl; flupenthixol 2 HCl, cis-(Z)-, fluspirilene; haloperidol; SCH-12679; SKF-83566; thioridazine HCl; thiothixine HCl; trifluoperazine 2HCl; and trifluorperidol HCl. Examples of suitable D1-like agonists include A-86929; 6-chloro-PB HBr, (xc2x1)-(SKF 81297); SKF 38393; A-69024, N-allylnorapomorphine HBr, R(xe2x88x92)-; apomorphine HCl, R(xe2x88x92)-; 6-bromo-APB HBr, r(+)-; 6-Chloro-APB HBr,(xc2x1)-(SKF-82958); Pergolide methanesulfonate, and SKF 77434. Such agonists or antagonists can be administered to the patient or animal at a dosage of 0.0001 mg/kg to 100 mg/kg of the body weight of the patient or animal, and more typically at a dosage of 0.1 to 1.0 mg/kg of the body weight of the patient or animal. In a typical method of administration, the D1-like antagonist or D1-like agonist is administered to the patient or animal orally, intravenously, or intramuscularly. Typically, an initial dosage of the D1-like antagonist or D1-like agonist will be administered to the patient within 0 to 24 hours of consumption of a psychostimulant or of nicotine by the patient, and potentially continued with a daily dose(s) for 1 to 365 days, or even life-long if desired.
A xe2x80x9cpsychostimulantxe2x80x9d is any agent having antidepressant or mood-elevating properties in a human, such as amphetamine and cocaine, or producing reinforcing effects during drug self-administration paradigms or conditioned-place preference paradigms in non-human animals.
A xe2x80x9ccompulsivexe2x80x9d psychostimulant or nicotine user is a person who has an irresistible impulse or strong craving to use a psychostimulant or nicotine, which typically is manifested as repetitive self-administration of the psychostimulant or nicotine.
A xe2x80x9cD1-like agonistxe2x80x9d is any compound that activates signal transduction via D1-like dopamine receptors or D1 dopamine receptors, typically by reversibly binding with its receptor and often with the resultant effect that is proportional to the number of receptors occupied. D1 agonists are encompassed by the term D1-like agonists as used herein.
A xe2x80x9cD1-like antagonistxe2x80x9d is any compound that interacts with D1-like or D1 dopamine receptors, or with other components of the D1 effector mechanism, to inhibit the action of an agonist while initiating no effect itself. D1 antagonists are encompassed by the term D1-like antagonists as used herein.
xe2x80x9cCravingxe2x80x9d is a monofocused motivational state, which occurs in the context of a perceived deficit of a reward. The degree of craving can be measured in terms of the behavior the person is willing to implement to get the objective of their motivational state.
The invention offers several advantages. By providing a method for inhibiting drug-induced craving, the invention provides an effective method for treating drug addictions (e.g., cocaine addiction). Because D1-like receptors are preferentially localized to the regions of the brain that mediate drug-induced craving (e.g., the nucleus accumbens and the amygdala), the use of D1-like agonists and antagonists provide specificity in targeting the appropriate regions of the brain. By using D1-like agonists in treating a patient, the patient may experience some sensations that are similar to those achieved through the use of the addictive drug (e.g., rush and high), without experiencing the withdrawal-related craving associated with cessation of drug use. The patient can experience non-psychostimulant-induced euphoria and/or reward, along with forming emotional memories of these experiences.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In the case of a conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative and are not intended to limit the scope of the invention, which is defined by the claims.